Tumor-activated lymph node fibroblasts suppress T cell function in diffuse large B cell lymphoma

被引：36

作者：

Apollonio, Benedetta ^{[1
,19
]}

Spada, Filomena ^{[2
]}

Petrov, Nedyalko ^{[2
]}

Cozzetto, Domenico ^{[3
,4
,5
]}

Papazoglou, Despoina ^{[1
]}

Jarvis, Peter ^{[11
]}

Kannambath, Shichina ^{[4
,6
]}

Terranova-Barberio, Manuela ^{[2
]}

Amini, Rose-Marie ^{[7
]}

Enblad, Gunilla ^{[7
]}

Graham, Charlotte ^{[1
]}

Benjamin, Reuben ^{[1
]}

Phillips, Elisabeth ^{[1
]}

Ellis, Richard ^{[2
]}

Nuamah, Rosamond

Saqi, Mansoor ^{[3
,4
]}

Calado, Dinis P. ^{[8
]}

Rosenquist, Richard ^{[9
]}

Sutton, Lesley A. ^{[9
]}

Salisbury, Jon ^{[10
]}

Zacharioudakis, Georgios ^{[11
]}

Vardi, Anna ^{[12
,13
]}

Hagner, Patrick R. ^{[14
]}

Gandhi, Anita K. ^{[14
]}

Bacac, Marina ^{[15
]}

Claus, Christina ^{[15
]}

Umana, Pablo ^{[15
]}

Jarrett, Ruth F. ^{[16
]}

Klein, Christian ^{[15
]}

Deutsch, Alexander ^{[17
]}

Ramsay, Alan G. ^{[1
,18
]}

机构：

[1] Kings Coll London, Fac Life Sci & Med, Sch Canc & Pharmaceut Sci, London, England

[2] Guys & St Thomass NHS Fdn Trust, BRC Adv Cytometry Platform, London, England

[3] Guys & St Thomass NHS Fdn Trust, BRC Translat Bioinformat, London, England

[4] Kings Coll London, London, England

[5] Imperial Coll London, Fac Med, Div Digest Dis, London, England

[6] Guys & St Thomass NHS Fdn Trust, BRC Genom Res Platform, London, England

[7] Uppsala Univ & Hosp, Dept Immunol Genet & Pathol, Uppsala, Sweden

[8] Francis Crick Inst, Immun & Canc Lab, London, England

[9] Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden

[10] Kings Coll Hosp NHS Fdn Trust, Dept Haematol, London, England

[11] Aristotle Univ Thessaloniki, Surg Dept 5, Thessaloniki, Greece

[12] G Papanikolaou Hosp, Hematol Dept, Thessaloniki, Greece

[13] G Papanikolaou Hosp, HCT Unit, Thessaloniki, Greece

[14] Bristol Myers Squibb, Summit, NJ USA

[15] Roche Innovat Ctr Zurich, Schlieren, Switzerland

[16] Univ Glasgow, MRC, Ctr Virus Res, Glasgow, Scotland

[17] Med Univ Graz, Div Hematol, Graz, Austria

[18] Guys Canc Ctr, Lymphoma Immunol, Innovat Hub, London SE1 9RT, England

[19] Ist Tumori Giovanni Paolo II, Dept Rare Tumors & Melanoma, Lab Tumor Immunol & Immunotherapy, Viale O Flacco 65, I-70124 Bari, Italy

来源：

JOURNAL OF CLINICAL INVESTIGATION | 2023年 / 133卷 / 13期

基金：

英国惠康基金; 英国医学研究理事会;

关键词：

RETICULAR CELLS; GENE-EXPRESSION; NICHE; PATHOGENESIS; SURVIVAL; STROMA;

D O I：

10.1172/JCI166070

中图分类号：

R-3 [医学研究方法]; R3 [基础医学];

学科分类号：

1001 ;

摘要：

Recent transcriptomic-based analysis of diffuse large B cell lymphoma (DLBCL) has highlighted the clinical relevance of LN fibroblast and tumor-infiltrating lymphocyte (TIL) signatures within the tumor microenvironment (TME). However, the immunomodulatory role of fibroblasts in lymphoma remains unclear. Here, by studying human and mouse DLBCL-LNs, we identified the presence of an aberrantly remodeled fibroblastic reticular cell (FRC) network expressing elevated fibroblast activated protein (FAP). RNA-Seq analyses revealed that exposure to DLBCL reprogrammed key immunoregulatory pathways in FRCs, including a switch from homeostatic to inflammatory chemokine expression and elevated antigen-presentation molecules. Functional assays showed that DLBCL-activated FRCs (DLBCL-FRCs) hindered optimal TIL and chimeric antigen receptor (CAR) T cell migration. Moreover, DLBCL-FRCs inhibited CD'+ TIL cytotoxicity in an antigen-specific manner. Notably, the interrogation of patient LNs with imaging mass cytometry identified distinct environments differing in their CD'+ TIL-FRC composition and spatial organization that associated with survival outcomes. We further demonstrated the potential to target inhibitory FRCs to rejuvenate interacting TILs. Cotreating organotypic cultures with FAP-targeted immunostimulatory drugs and a bispecific antibody (glofitamab) augmented antilymphoma TIL cytotoxicity. Our study reveals an immunosuppressive role of FRCs in DLBCL, with implications for immune evasion, disease pathogenesis, and optimizing immunotherapy for patients.

引用

页数：23

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